Abstract: Why do some individuals who are exposed to Mycobacterium tuberculosis become infected, while others do not? Of those who are exposed and infected, why do some individuals rapidly progress to active disease, while others remain asymptomatic, latently infected, or progress to active disease decades later or not at all? The observed heterogeneity in individuals'responses to exposure and infection might be explained by differences in the transmission characteristics of M. tuberculosis and its virulence in the human host. Our goals are to 1) identify the gene expression profiles of M. tuberculosis in sputa from patients with latent TB infection and active disease;2) identify sets of genes that characterize the early infection, pro-inflammatory immune response post-infection, and active disease stages of M. tuberculosis in the human host, and 3) identify differential gene expression patterns attributable to different strains, including drug-resistant and pan-susceptible strains of M. tuberculosis. We propose a case-control study of tuberculosis patients, their infected and uninfected contacts, and neighborhood healthy controls. From enrolled study participants, we will obtain information, a cough sample with sputa, and a blood sample. The sets of gene expression patterns- diagnostic signatures-could be translated into new, accurate and rapid diagnostic tests. We will recruit and enroll patients in Shanghai, China, a city with over 6,000 new TB cases annually and the point of departure for many migrants to the United States. Our discoveries will have a significant impact on the tuberculosis epidemic worldwide, a global health emergency that caused 9.2 million new cases and killed 1.7 million persons in 2006. We seek strategies to target scarce public health resources to prevent new cases of active tuberculosis in the United States and globally. Public Health Relevance: Tuberculosis (TB) is a global health problem and it is one of the leading causes of death due to an infectious disease. The rates of drug-resistant TB are increasing worldwide and could reverse the decreasing trend of TB disease and death. We want to learn how the pathogen Mycobacterium tuberculosis successfully transmits through the air to cause new infections, and how we can rapidly detect and prevent its spread.